GB1595119A - 2-hydroxycyclopentaneacetic acid y-lactones and processes for producing them - Google Patents

Description

PATENT SPECIFICATION ( 11) 1 595-119

X ( 21) Application No 42937/79 ( 22) Filed 26 May 1978 _ ( 62) Divided out of No1595118 ( 19 ( 31) Convention Application No 52/064217 11 ( 32) Filed 31 May 1977 ( 31) Convention Application No 52/107642 ( 32) Filed 6 Sept 1977 in I ( 33) Japan (JP) ( 44) Complete Specification published 5 Aug 1981 ( 51) INT CL 3 C 07 D 307/77 407/12 (C 07 D 407/12 307/77 309/12) ( 52) Index at acceptance C 2 C 147 X 1672 200 2 i 3 215 220 22 Y 247 248 253 259 25 Y 28 X 294 295 305 30 Y 314 31 Y 338 350 351 352 355 35 Y 360 361 362 364 366 367 368 36 Y 387 388 389 401 409 40 Y 43 X 46 Y 490 491 500 503 509 50 Y 623 625 628 633 634 635 638 652 655 658 65 X 665 672 67 X AA TA TU ( 54) 2-HYDROXYCYCLOPENTANEACETIC ACID y-LACTONES AND PROCESSES FOR PRODUCING THEM ( 71) We, SUMITOMO CHEMICAL COMPANY LIMITED, a corporation organized under the laws of Japan, of 15, Kitahama 5 chome, Higashi-ku, Osaka, Japan, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: 5

The present invention relates to intermediates useful for the preparation of prostadienoic acid derivatives and the the production of these intermediates.

More particularly, the invention relates to 2 hydroxy cyclopentaneacetic acid y lactones and to a process for their preparation.

The present invention provides a 2 hydroxycyclopentane acetic acid y 10 lactone compound of the formula (II); RO (II) o< R 6 wherein R is a hydrogen atom or a hydroxy-protecting group and Y is CHO, CH=CHCOR 2 or CH=CHCHR 2 15 OR (wherein R 2 is C 4 _ 8 alkyl and R is a hydrogen atom or a hydroxyprotecting group and is preferably hydrogen).

Compounds within the formula lIIl are useful as intermediates for the preparation of prostadienoic acid derivatives of the formula lIl.

Z H C R 1 20 HO)R 2 R 2 (I) wherein R, is a hydrogen atom or a C 1 _ 4 alkyl group, R 2 is C 4 _ 8 alkyl and OH C=Z is C=O or C / / /H H These prostadienoic acid derivatives of the formula lIl and their preparation are described and claimed in our copending UK Patent Application No 23537/78 (Serial No 1595118) 5 In this specification, the term "C 14 alkyl" means an alkyl group having from one to four carbon atoms (e g, methyl, ethyl, isopropyl, t butyl) and the term "C 48 alkyl" means a straight or branched chain alkyl group having from four to eight carbon atoms (e g, pentyl, butyl, a methylpentyl).

The hydroxy-protecting group in a compound of the formula lIIl is preferably 10 a 2 tetrahydropyranyl group or an acyl group, for example, acetyl, propionyl, benzoyl and p phenylbenzoyl.

Prostadienoic acids within the formula (I), which can be prepared from compounds embodying this invention, have various useful pharmacological activities and are useful as antiulcer agents and gastric secretion inhibitors In 15 particular they possess anti-gastrointestinal ulcer activity That is, they inhibit excessive secretion of gastric acid, and thereby inhibit the formation of gastrointestinal ulcers or heal ulcers in mammals.

A prostadienoic acid (I) can be prepared as follows:

(I) If the prostadienoic acid is of the formula llal 20 OH 0 U 2 of the formula (III) OHOH OR 8 25 R O (m I) nu wherein R 2 isand R are as defined above and R 8 is hydrogean or tetrahydropyranyl, withcting a compound (directly obtained from the intermediate lactone (II) as later described) compound of the formula (III(IV); (R 3)3 P=CH(CH 2)3 COOM lIVl H R 2 25 R 80 wherein R 2 is as defined above and R 8 is hydrogen or tetrahydropyranyl, with a compound of the formula (IV); (R 3)3 P=CH(CH 2) COOM lIV wherein R 3 is an aryl group and M is an alkali metal and optionally subsequently esterifying and/or hydrolysing the resultant product 30 The Wittig reaction can be carried out in the presence of solvent using from I-10 molar equivalents (preferably from 2-4 molar equivalents) of the Wittig reagent (IV) per molar equivalent of the compound lIIIl Examples of the solvent are ethers (e g, diethyl ether, tetrahydrofuran, dioxane), hydrocarbons (e g, benzene, toluene, hexane) and dimethyl sulfoxide 35 The reaction can, in general, be effected at room temperature, but it can be controlled with warming or cooling depending upon the extent of progress The reaction time may vary depending upon the reaction temperature and the reagent to be used therein but is generally from 2-30 hrs.

1,595,119 J,9,1 73 The prostadienoic acid thus obtained can be separated from the reaction mixture and the prostadienoic acid thus obtained can be esterified (R, is C,_ 4 alkyl) and, if R 8 is 2 tetrahydropyranyl, is hydrolyzed and purified by conventional procedures.

( 2) If the prostadienoic acid is of the formula lIbl; HO-COOR I,v'- / '-R 2 HO wherein R, and R 2 are as defined above, this can be prostadienoic acid of the formula lIcl; OH OR 9 R 90 R 90 (lb) prepared by oxidizing a (Ic) wherein R, and R 2 are as defined above and R 9 is a 2 tetrahydropyranyl group (this being a compound of the formula lIal in which the hydroxyl groups in the 11 a and 16 positions thereof have been protected with the 2 tetrahydropyranyl group), and reproducing the hydroxyl groups by hydrolysis.

The oxidizing agent preferably used in this reaction is Collins reagent (Cr O 3 pyfidine 2) or a Moffatt reagent (e g, dimethyl sulfoxide dicyclohexylcarbodiimide pyridine trifluoroacetic acid) The reaction can be carried out by the same procedure as that described in J Am Chem Soc, 96 5876-5893 ( 1974) A 2 hydroxycyclopentane acetic acid p lactone (II) embodying the invention can be prepared by the following methods:

2) E ( 2) COOH 'COOR 4 \r COOR 4 HOOC ( 4) O Ac -CO OR 4 COOR 4 O Ac ( 6) _, l COOR 4 u COOR 4 ( 31 COCH 3 COOR 4 COOR 4 COCH 3 ( 5) 0 o H ( 1 COOR 4 HO ( 7) 0 OH ("OH ( 1) 1,595,119 A 4 1,595,119 4 PA <OiCOORS HO ( 8) HO 0-l CH 2 OH RO ( 10) l' R 2 ( 11 b) COO Rs RO ( 9) o' ILC HO RO ( 11 Q) R 2 (it) RU ( 11 c) wherein R 2 and R are as defined above, R 4 is C,_ 4 alkyl, Ac is acetyl and R 5 is an optionally substituted phenacyl group.

A compound ( 3) is obtained from the compound ( 1) by the sequential steps of tosylation, cyanation, hydrolysis and esterification The transformation of the compound ( 3) to a compound ( 5) is carried out by oxidation, chlorination, diazotization and reduction The Baeyer-Villiger oxidation of the compound ( 5) gives a diacetoxy compound ( 6) Acid hydrolysis of the compound ( 6) gives a lactone carboxylic acid ( 7) The compound ( 7) is treated with a phenacyl halide derivative to give a compound ( 8).

Acylation of the compound ( 8) gives a compound ( 9) The transformation of the compound ( 9) to a compound ( 10) can be carried out by dephenacylation and reduction substantially the same procedure as that disclosed in Tetrahedron Letters No 19, 1629-1632 ( 1977).

A compound (Ila) can be obtained by oxidizing the compound ( 10) The oxidation of the compound ( 10) to the compound (I Ia) can be carried out in the same manner as the oxidation of the compound (Ic) to the compound (Ib).

A compound (Ib) is obtained from the compound (Ila) by reacting the compound (I Ia) with an ylid of the following formula (V).

(Me O)2 P-CHCOR 2 0 (V) wherein R 2 is as defined above.

This reaction can be carried out by a conventional procedure as disclosed, for example, in J Am Chem Soc, 96, 5876-5893 ( 1974).

A compound (I Ic) can be obtained by the reduction of the compound (l Ib) with a reducing agent such as an alkali metal borohydride (e g, sodium borohydride) or aluminium alkoxide (e g, aluminium triisopropoxide), in a conventional manner.

1.595 119 A 1,595,119 Method B:

CH 2 COO Me CN Cl ( 11) HO CN ( 13) OHC Cl CN ( 14) R 2 > -04 Cl CN ( 15) ( 16) Il OH I R' 2 HO ( 18) 117) 0 WAS < OH HO R 2 d) HO (E d) wherein R 2 is as defined above.

The Diels-Alder reaction of the cyclopentadiene derivative ( 11) with a chloroacrylonitrile at 0 C gives the norbornene derivative ( 12), which is reduced with calcium borohydride to give the alcohol derivative ( 13).

The compound ( 13) is oxidized with Collins-reagent (Cr O 3 pyridine 2) to give the aldehyde ( 14) followed by reacting with an ylid of the compound (V), (Me O)2 P-CHCOR 2 (V) wherein R 2 is as defined above, to give an enone ( 15).

The transformation from the compound ( 15) to a compound ( 17) is carried out by reduction and alkaline hydrolysis The compound ( 17) is treated with alkaline hydrogen peroxide solution and subsequently with iodine to give an iodilactone derivative ( 18).

The compound ( 18) is treated with tributyltin hydride to give the compound (I Id).

A cyclopentalbl furan 2 ol of the following formula (III); OH R 8 < (R 2 Rs O ( 1) wherein R 8 and R 2 are as defined above, may be prepared by the following method:

A 2 hydroxycyclopentane acetic acid y lactone of the formula (lid) 0 oOH HO (EI d) wherein R 2 is as defined above, which is obtained by the method B or hydrolysis of the compound of the formula (I Ic) obtained by method A, 5 0 R 2 HO (I 1) HO is treated with diisobutylaluminium hydride to give a compound (III) wherein R 8 is hydrogen.

Alternatively the compound (lid) is treated with dihydropyran followed by reduction with diisobutyl aluminium hydride to give a compound (III) wherein R 8 is 10 2 tetrahydropyranyl.

A prostadienoic acid ( 1), which can be prepared from an intermediate embodying this invention as previously described, may be administered effectively orally, sublingually, or intravenously at a daily dosage of about 1 to 100 mg/kg as a gastric secretion inhibitor and antiulcer agent 15 The following Examples illustrate methods of (i) preparing precursors from which an intermediate lactone within the formula (II) and embodying the invention can be obtained (Examples 1-7, 10 and 11), (ii) obtaining such an intermediate lactone by a process embodying the 20 invention (Example 8), (iii) converting this lactone, by processes embodying the invention or optional additional steps, into other intermediate lactones within the formula (II) (Examples 9, 12 and 13), (iv) converting such an intermediate lactone into a compound within the 25 formula (III), from which prostadienoic acid derivative within the formula (I) can be prepared (Example 14-step 1), (v) preparing such prostadienoic acid derivatives (Example 14 (steps 2-3) and 15-6).

Example 1 30 exo-2-Cyanomethyl-endo-3-cyanomethylbicyclo-l 2,2,1 lhept-5-ene.

To a solution of exo 2 hydroxymethyl endo 3 hydroxymethylbicyclol 2,2,1 lhept 5 -ene ( 3 08 g) in pyridine ( 10 ml), was added a solution of p toluenesulfonyl chloride ( 7 7 g) in dry benzene ( 10 ml) at O C After stirring overnight at room temperature, benzene ( 100 ml) was added to this solution 35 The organic layer was separated and washed with water, 10 % hydrochloric acid, aqueous sodium bicarbonate and water and then dried over magnesium sulfate.

Evaporation of the solvent gave the crystalline ditosylate compound ( 9 0 g).

To a solution of this tosylate ( 9 0 g) in anhydrous dimethyl sulfoxide, was added sodium cyanide ( 4 g) and heated at 100 C for 1 5 hr 40 Benzene and water was added to the reaction mixture and, after equilibration, the organic layer was washed with water, dried, and evaporated to give the desired dicyano compound ( 3 1 g) as an oil.

IR vflm cm-': 2950, 2250, 1420, 1340.

NMR (CC 14) 8: 6 0-6 5 ( 2 H, m, olefinic protons) 45 1,595,119 Example 2 exo-2-endo-3-Bismethoxycarbonylmethylbicyclol 2,2,1 l hept-5-ene.

The cyano compound ( 10 g) obtained by the procedure of Example 1, was refluxed for 5 hr in 20 % aqueous potassium hydroxide The reaction mixture was acidified with 10 % hydrochloric acid and extracted with ethyl acetate The organic 5 extract was washed with water, dried, and evaporated to give a crystalline dicarboxylic acid compound (m p 162 C) This acid was dissolved in dry methanol and a few drops of concentrated sulfuric acid was added After stirring overnight, the solution was neutralized with sodium bicarbonate and the methanol was evaporated The residue was extracted with benzene and the extract was distilled to 10 give 9 5 g of the desired product (b p, 106 -110 C/0 2 mm Hg).

IR vfilm acm-1: 1740, 1440, 1150.

NMR (CC 14) a: 5 8-6 4 ( 2 H, m), 3 65 ( 6 H, S).

Example 3

1 a,4 a-Diacetyl-2 a,3/p-bismethoxycarbonylmethylcyclopentane 15 The diester ( 10 g), prepared by the procedure of Example 2, was dissolved in dry benzene ( 200 ml) and crown ether (dibenzo 18 crown 6) ( 500 mg) and potassium permanganate ( 22 g) were then added After stirring overnight at room temperature, water ( 50 ml) was added and the mixture stirred for another 30 minutes The mixture was filtered and the benzene layer of the filtrate was 20 separated The aqueous phase was acidified with concentrated hydrochloric acid to p H 1, and was extracted with ethyl acetate Evaporation of ethyl acetate gave 9 6 g of the desired dicarboxylic acid.

This acid ( 9 6 g) was suspended in dry benzene ( 150 ml) and dry dimethylformamide ( 1 ml), and then 20 % phosgene in toluene solution ( 30 ml) was 25 added with cooling.

The reaction mixture was stirred at room temperature and was concentrated under reduced pressure to give an acid chloride.

To an etheral solution of diazomethane, was added a solution of the acid chloride prepared above in diethyl ether and the mixture stirred for 3 hr at room 30 temperature.

Evaporation of the ether gave a bis diazoketone compound.

This diazoketone was dissolved in chloroform ( 70 ml) and treated with 50 %o hydroiodic acid ( 10 ml).

After equilibration, the chloroform layer was washed with water, dried and 35 concentrated to give a crude oil, which was chromatographed on silica gel to afford the desired diacetyl compound ( 3 2 g).

IR fvlmx cm-': 1740, 1710, 1440,1360, 1260.

NMR (CC 14) 8: 3 6 ( 6 H, S), 2 13 ( 6 H, S).

Example 4 40

1 a,4 a-Diacetoxy-2 a,3 p-bismethoxycarbonylmethylcyclopentane.

To a mixture of the diacetyl compound ( 1 5 g), prepared by the procedure of Example 3, in dichloromethane ( 60 ml) and disodium hydrogen phosphate ( 6 7 g), was added a solution of 90 % hydrogen peroxide ( 1 28 ml) and trifluoroacetic anhydride ( 9 8 g) under gentle reflux 45 After stirring for 2 hr at room temperature, the reaction mixture was filtered and washed with chloroform.

The filtrate was washed with aqueous sodium bicarbonate and water, dried and evaporated to give the desired diacetoxy compound ( 1 48 g) as an oil.

IR vlamcm-': 1740,1440,1370,1240,1160,1070,1020 50 NMR (CC 4) 8: 4 7-5 3 ( 2 H, m), 3 6 ( 6 H, S), 2 0 ( 6 H, S).

Example 5

2 a,4 a-Dihydroxy-5/3-carboxymethylcyclopentanela-acetic acid p-lactone.

la,4 a Diacetoxy 2 a,3/3 bis methoxycarbonylmethylcyclopentane ( 300 55 mg) obtained by the procedure of Example 4 was heated in concentrated hydrochloric acid ( 2 0 ml) for 2 hr and evaporated under reduced pressure.

The residue was extracted with ether and concentrated to give a crystalline lactone ( 160 mg).

IR Nua Jo' cm-l: 1780, 1710, 1420,1200,1080,1040 60 "Nujol" is a registered Trade Mark.

1,595,119 Example 6

2 a-Hydroxy-4 a-acetoxy-5/3-carboxymethylcyclopentanela-acetic acid y-lactone.

2 a,4 a Dihydroxy 5/5 carboxymethylcyclopentane la acetic acid y lactone ( 100 mg) prepared by the procedure of Example 5 was dissolved in water ( 2 5 ml) and an equivalent of 5 % aqueous sodium hydroxide solution was added thereto.

A solution of p bromophenacyl bromide ( 160 mg) in methanol ( 5 ml) was added to this solution.

After refluxing for 1 5 hr, the solvent was distilled off.

The residue was extracted with ethyl acetate, dried and concentratedto give 10 an oily phenacyl ester ( 160 mrag).

I Rv-'mx cm-': 1760, 1740, 1700,1590,1420, 1400, 1370, 1170 The phenacyl ester, prepared above, was acetylated with acetic anhydride ( 100 mg) in pyridine ( 2 ml).

After chromatography on silica gel, the desired acetate was obtained as an oil 15 ( 155 mg).

I Rv/Im cm-': 1770, 1740, 1700, 1590, 1420, 1400 The acetate compound prepared above was dissolved in acetic acid ( 10 ml) and zinc powder ( 1 g) was added.

After stirring for 2 hr at room temperature, the reaction mixture was filtered 20 The filtrate was concentrated in vacuo and to the residue was added diethyl ether and aqueous sodium bicarbonate.

After equilibration, the aqueous phase was acidified with diluted sulfuric acid to p H 1 and extracted several times with dichloromethane.

Evaporation of the solvent gave a crystalline carboxylic acid ( 60 mg, m p 25 108-1 10 C).

I Rv/Nuol cm-: 1770,1740,1710,1440, 1340,1230,1180,1040 "Nujol" is a Registered Trade Mark Example 7

2 a-Hydroxy-4 a-acetoxy-5/l-( 2 '-hydroxyethyl)-cyclopentane 30 la-acetic dcid y-lactone.

2 a Hydroxy 4 a acetoxy 5/P carboxymethylcyclopentane I a acetic acid y lactone ( 50 mg) prepared by the procedure of Example 6 was treated with excess diborane in tetrahydrofuran at 0 -100 C.

After I hr, the reaction mixture was quenched with acetone and evaporated in 35 vacuo.

Chloroform and saturated aqueous ammonium chloride were added to this residue.

The organic layer was separated and evaporated to give the desired alcohol ( 45 mg) as an oil 40 IR vfim cm-': 3450, 1770, 1730, 1360, 1240, 1160, 1020.

NMR(CCI 4)8: 4 8-5 2 ( 2 H, m), 3 7 ( 2 H, t), 2 0 ( 3 H, S).

Example 8

2 a-Hydroxy-4 a-acetoxy-5/3-( 4-oxo-trans-2nonenyl)-cyclopentane-la-acetic acid y-lactone 45 The alcohol compound ( 50 mg) prepared by the procedure of Example 7, was oxidized with chromic anhydride dipyridine complex in dichloromethane ( 10 ml) and diethyl ether was then added.

The reaction mixture was filtered and the filtrate was concentrated to give the desired aldehyde derivative as an oil 50 This aldehyde was added at ambient temperature to the reagent prepared from dimethyl 2 oxo heptylphosphonate and 50 % sodium hydride in dimethoxyethane.

After stirring for 2 hr, the reaction mixture was neutralized with acetic acid and evaporated 55 The residue was extracted with diethyl ether and evaporation of the ether gave an oil, which was chromatographed on silica gel, to afford the desired enone ( 65 mg).

IR v Iax cm-': 1770, 1730, 1700, 1660,1620, 1460, 1360, 1220, 1040.

1,595,119 Example 9

2 a-Hydroxy-4 a-acetoxy-5/p-( 4-hydroxy-trans-2nonenyl)cyclopentane-la-acetic acid y-lactone.

The enone compound ( 50 mg), prepared by the procedure of Example 8, was treated with sodium borohydride in methanol at O C 5 The reaction mixture was quenched with acetone and evaporated.

To the residue was added ether and aqueous ammonium chloride.

The ether extract was washed with water, dried and concentrated to give the desired alcohol ( 45 mg) as an oil.

I Rvcfilmcm-': 3500, 1770, 1190, 1130, 1080 10 Example 10

2-Chloro-2-cyano-7-methoxycarbonylmethylbicyclol 2,2, 1 llhept-5-ene.

2,4 Cyclopentadienyl acetic acid methyl ester was prepared from the sodium salt of cyclopentadiene and methyl bromoacetate in tetrahydrofuran by the method of J J Partridge lJ Am Chem Soc, 95, 7171 ( 1973)l 15 A solution of the diene obtained above in a chloroacrylonitrile ( 5 ml) was added to a mixture of a chloroacrylonitrile ( 10 ml) and anhydrous cupric fluoroborate ( 1 5 g) at O C The reaction mixture was stirred for 20 hr at 0-5 C.

The mixture was concentrated in vacuo and the oily residue obtained was dissolved in diethyl ether The ether solution was washed with aqueous sodium 20 tartrate and brine and then dried Evaporation of the solvent gave a crude oily product which was chromatographed on silica gel using benzene as eluent to afford the desired adduct ( 3.8 g).

IR v'il cm-': 2950,2240, 1740, 1440,1330, 1165 25 NMR (CC 14) 8: 6 33 ( 1 H, d,d), 6 01 (IH, d, d), 3 63 ( 3 H, s).

Example 11

2-Chloro-2-cyano-7-( 2-hydroxyethyl)bicyclol 2,2,1 lhept-5-ene.

An ethanol solution of the adduct ( 500 mg) prepared by the procedure of Example 10 was added to a mixture of four equivalents of sodium borohydride, 30 three equivalents of powdered calcium chloride and ethanol ( 20 ml) at room temperature under nitrogen.

After stirring for 3 hr, the reaction mixture was quenched by adding aqueous ammonium chloride and was extracted with chloroform.

The organic layer was washed with brine, dried and evaporated to give an oily 35 residue, which was chromatographed on silica gel to afford the desired alcohol ( 300 mrg).

IR vfl, cm-': 3600, 3200, 2950, 2250, 1450, 1345, 1060.

V ax NMR (CC 14) 8: 6 28 (IH, d,d), 5 97 (IH, d,d).

Example 12 40

2 a,4 a-dihydroxy-5 p 3-( 4-hydroxy-trans-2nonenyl)cyclopentane-la-acetic acid y-lactone.

The acetoxy compound ( 150 mg) obtained by the procedure of Example 9 was dissolved in methanol ( 3 ml) and potassium carbonate ( 50 mg) was added to this solution After stirring for 1 hr at room temperature, the reaction mixture was 45 neutralized with I N hydrochloric acid and then evaporated in vacuo The residue was extracted with ethyl acetate The extract was washed with brine and dried and then evaporated to give an oil, which was chromatographed on silica gel with a benzene ethyl acetate mixture ( 1:3) as an eluent.

The desired diol-lactone derivative ( 112 mg) was obtained as an oil 50 IR Vflam cm-: 3400, 3060, 2950, 2850, 1770, 1460, 1380, 1340, 1260,1180.

Example 13

2 a-Hydroxy-4 a-tetrahydropyran-2 '-yloxy-5/-l 4-(tetrahydropyran-2 'yloxy)-trans-2-nonenyllcyclopentane1 la-acetic acid y-lactone 55 To a solution of the diol compound ( 110 mg) prepared by the procedure of Example 12 in methylene chloride ( 2 ml), were added 2,3 dihydropyran ( 50 mg) and p toluenesulfonic acid ( 10 mg) After stirring for 30 minutes at room 1,595,119 temperature, the reaction mixture was neutralized with aqueous sodium bicarbonate and diluted with ethyl acetate After equilibration, the organic layer was washed with water and brine Evaporation of the solvent gave the desired tetrahydropyranylether compound ( 113 mg).

IR vfax cm-: 2950, 1775,1490 5 Example 14

9 a-Hydroxy 11 a, 16-bis(tetrahydropyran-2 '-yloxy)-20-methylcis-5, trans-14-prostadienoic acid methyl ester.

Step I The tetrahydropyranyl compound ( 100 mg) obtained by the procedure of 10 Example 13 was dissolved in dry toluene ( 5 ml) and 15 % diisobutylaluminium hydride in toluene solution ( 3 ml) was added dropwise at -70 C After stirring for minutes at the same temperature, the mixture was quenched by adding methanol carefully until the evolution of gas ceased The resulting mixture was allowed to warm to 0 C and water ( 1 ml) was added After stirring for another 30 minutes, the 15 mixture was filtered and the filtrate was separated The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give a hemiacetal (i e, a cyclopentalblfuran 2 ol) ( 93 mg) as an oil.

Step 2 A mixture of 50 % sodium hydride in mineral oil ( 96 mg) and dimethyl sulfoxide 20 ( 10 ml) was stirred under nitrogen at 70-75 C for I hour To the methylsulfinyl carbanoin thus obtained was added a solution of ( 4 carboxybutyl)triphenylphosphonium bromide ( 443 mg) in dimethyl sulfoxide ( 5 ml) at 20 C After 5 minutes, to this solution was added the hemiacetal prepared above, in dimethyl sulfoxide ( 2 ml) and the resulting solution was stirred at room 25 temperature for 3 hr To the reaction mixture was added a mixture of ethyl acetate and water and the organic layer was separated.

The aqueous phase was then acidified to p H 1 with dilute hydrochloric acid and was extracted with ethyl acetate Evaporation of the solvent gave an oil.

Step 3 The oil was dissolved in tetrahydrofuran and treated with ethereal 30 diazomethane After evaporation, the resulting residue was chromatographed on silica gel to give the desired methyl ester derivative ( 98 mg).

IR viml cm-': 3350, 2930, 1735, 1280.

Example 1535

9 a, 11 a, 16-Trihydroxy-20-methyl-cis-5,trans 14prostadienoic acid methyl ester.

9 a Hydroxy 11 a,16 bis(tetrahydropyran 2 ' yloxy) 20 methyl cis 5,trans 14 prostadienoic acid methyl ester ( 80 mg) obtained by the procedure of Example 14 was dissolved in a mixture of acetic acid 40 tetrahydrfofuran water ( 10:3:10) ( 10 ml) and heated at 50 C for 3 hr After evaporation, the residue was chromatographed on silica gel to give the desired triol compound ( 35 mg).

IR vfilm cm-: 3450, 2950, 1935, 1280 Example 16 45

9-Oxo 11 a, 16-dihydroxy-20-methyl-cis-5,trans 14prostadienoic acid methyl ester.

9 a Hydroxy 11 a,16 bis(tetrahydropyran 2 ' yloxy) 20 methyl cis 5,trans 14 prostadienoic acid methyl ester ( 95 mg) obtained by the procedure of Example 14 was dissolved in methylene chloride To this solution was 50 added a solution of two equivalents of Collins reagent in methylene chloride After stirring at room temperature for 10 minutes, diethyl ether was added and the mixture was filtered through-Cefite ("'Celte" is a Registered Trade Mark) The filtrate gave, after evaporation, a crude 9 oxo 11 a, 16 bis(tetrahydropyran 2 ' yloxy) 20 methyl cis 5,trans 14 prostadienoic acid methyl ester ( 88 55 mrg).

IR vilax cm-': 3450, 2950,1740, 1280 1,595,119 l O The crude compound prepared above was dissolved in a mixture of acetic acid tetrahydrofuran water ( 65:10:35) ( 10 ml) and stirred at 45 C for 3 hr The reaction mixture was concentrated in vacuo and to the residue was added ethyl acetate and water The organic layer was separated, washed with brine, dried and evaporated to give an oil, which was chromatographed on silica gel to afford the 5 desired methyl prostate derivative.

I Rvfil cm-1: 3450, 2995, 2950, 1740, 1730, 1480 1380, 1250.

Claims (9)

WHAT WE CLAIM IS:-

1 A compound of the formula 10 RO wherein R is hydrogen or a hydroxy-protecting group and Y is formyl, CH=CHCOR 2 or CH=CH-CHR 2 I OR (wherein R 2 is C 4 _ 8 alkyl and R is as defined above).

2 A compound of the formula given and defined in claim 1, wherein Y is 15 CH=CH-CHR 2.

OH

3 A process for producing a 2 hydroxycyclopentanacetic acid y lactone of the formula CHO R 16 wherein R' is a hydroxy-protecting group, which comprises oxidizing an alcohol 20 derivative of the formula IO X, <.EH 20 H K Rib wherein R' is as defined above, with an oxidizing agent.

4 A process for producing a 2 hydroxycyclopentaneacetic acid y lactone of the formula 25 OH 0 HOR 2 1 OA H O 1,595,119 wherein R 2 is C 4 _ 8 alkyl, which comprises reducing a 2 hydroxycyclopentaneacetic acid y lactone of the formula <-,<' R 2 RO wherein R 2 is as defined above and R is hydrogen or a hydroxy-protecting group, with a reducing agent, and when R is a hydroxy-protecting group, hydrolysing prior

5 or subsequent to reduction to convert the said group R to a hydrogen atom.

A process according to claim 4, wherein the reducing agent is a metal borohydride.

6 A process for producing a 2 hydroxycyclopentaneacetic acid y lactone of the formula CH = CHCOR 2 RO wherein R 2 and R are as defined in claim I, which comprises reacting a compound of the formula given and defined in claim 1 wherein Y is specifically formyl with an ylid of the formula (Me O)2 P-CHCOR 2 15 1 wherein R 2 is as defined in claim 1.

7 Compounds of the formula given and defined in claim I which are specifically disclosed herein.

8 Processes according to any one of claims 3 to 6 for producing a compound of the formula given and defined in claim 1, which processes are substantially as 20 herein described and exemplified.

9 Compounds of the formula given and defined in claim I whenever prepared by a process according to any one of claims 3 to 6 and 8.

MEWBURN ELLIS & CO, & 72 Chancery Lane, London, WC 2 A l AD.

Agents for the Applicants.

Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.

1,595,119